N,n'-2,4-dianilinopyrimidine derivatives, preparation thereof as drugs, pharmaceutical compositions essentially as ikk inhibitors

Abstract

The disclosure relates to a compound of formula (I): wherein R, R1, R2, R3, R4, R5, R6 and Z are as defined in the specification, to compositions containing them, to processes for preparing them, and to their use in the treatment or prevention of conditions capable of being modulated by the inhibition of the activity of protein kinases.

1 ) A compound of formula (I): 
     
       
         
         
             
             
         
       
       wherein: 
       R represents a hydrogen or halogen atom; 
       R2, R3 and R4, which may be identical or different, are such that one of R2, R3, and R4 represents a halogen atom or CF 3  and the other two, which may be identical or different, represent a hydrogen atom or a halogen atom or an alkyl radical or an alkoxy radical optionally substituted with one or more halogen atoms; 
       R5 represents a hydrogen atom or a halogen atom; 
       Z represents CO or SO 2 ; 
       the ring (N): 
     
     
       
         
         
             
             
         
       
     
     is substituted on the same carbon atom with R1 and R6, contains 4 to 7 ring members, is saturated and optionally contains a carbon-based bridge consisting of 1 to 3 carbons;
 R1 and R6 represent one of the following 6 alternatives i) to vi): 
 i) R1 represents —X1-R7, wherein X1 represents —(CH 2 ) m — and R7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted; 
 and R6 represents a hydrogen atom, or a hydroxyl, methyl, methoxy, —(CH 2 ) m OH, —CO—NRaRb, —CH 2 —NRaRb, —CO 2 H or —CO 2 alk radical; 
 ii) R1 represents —X2-R7, wherein X2 represents: —O—, —O—(CH 2 ) m —, —CH(OH)—(CH 2 ) n —, —CO—, —CO—NRc-, —CO—NRc-O—, —CH(NRaRb)—, —C═NOH—, —C═N—NH 2 —, or —(CH 2 ) n1 —NRc-(CH 2 ) n2 —; and 
 wherein R7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted; 
 and R6 represents hydrogen or the methyl radical; 
 iii) R1 represents —NRc-W, wherein W represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms which is linear or branched from 3 carbon atoms and optionally substituted with a radical chosen from —PO(OEt) 2 , —OH, —Oalk, —CF 3 , —CO—NR8R9 and SO 2 -alk; and R6 represents hydrogen; 
 and wherein when W represents a hydrogen atom, then z represents CO; 
 iv) R1 represents —CH 2 —NRc-W, wherein W represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms which is linear or branched from 3 carbon atoms and optionally substituted with a radical chosen from —PO(OEt) 2 , —OH, —OEt, —CF 3 , —CO—N(alk) 2  and SO 2 -alk; and R6 represents hydrogen; 
 v) R1 represents —CO—N(Rc)-OR′c and R6 represents hydrogen; or 
 vi) R1 represents X3-R7, wherein X3 represents —CH(OH)—(CH 2 ) n —, —CO—, —CH(NRaRb)—, —C═NOH—, or —C═N—NH 2 —; 
 and wherein R7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted; 
 and R6 represents a hydrogen atom or a hydroxyl, methyl, methoxy, —(CH 2 ) m OH, —CO—NRaRb, —CH 2 —NRaRb or —CO 2 alk radical; 
 n, n1 and n2, which may be identical or different, represent an integer from 0 to 3; 
 m represents an integer from 1 to 3; 
 Rc and R′c, which may be identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms, optionally substituted with one or more halogen atoms; 
 NRaRb is such that either Ra and Rb, which may be identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms or a cycloalkyl radical, the alkyl and cycloalkyl radicals being optionally substituted with one or more halogen atoms, a hydroxyl radical or an NH 2 , NHalkyl or N(alkyl) 2  radical; 
 or Ra and Rb form, with the nitrogen atom to which they are attached, a cyclic amine that may optionally contain one or two other heteroatoms chosen from O, S, N or NR10, the cyclic amine thus formed itself being optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and the radicals oxo, hydroxyl, and alkyl, themselves optionally substituted with one or more halogen atoms, or with a methyl radical or a hydroxyl radical on the same carbon; and wherein 
 all of the heterocycloalkyl, aryl and heteroaryl radicals being optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms, hydroxyl, cyano or NR8R9 radicals; and the radicals alkyl, cycloalkyl, alkoxy, phenyl, heterocycloalkyl and heteroaryl, themselves optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and the radicals hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CN, CF 3 , OCF 3  or NRaRb; 
 R8 represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms or a cycloalkyl radical, these alkyl and cycloalkyl radicals being optionally substituted with one or more halogen atoms, a hydroxyl radical or an NH 2 , NHalkyl or N(alkyl) 2  radical; 
 R9 represents a hydrogen atom or the radicals alkyl, cycloalkyl or heterocycloalkyl, themselves optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and the radicals hydroxyl, alkoxy, NH 2 , NHalkyl or N(alkyl) 2 , the alkyl radicals represented by R9 also being optionally substituted with a phenyl, heterocycloalkyl or heteroaryl radical, itself optionally substituted with one or more radicals chosen from halogen atoms and the radicals hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CN, CF 2 , OCF 2 , NH 2 , NHalk and N(alk) 2 ; 
 or R8 and R9 form, with the nitrogen atom to which they are attached, a cyclic amine that may optionally contain one or two other heteroatoms chosen from O, S, N or NR10, the cyclic amine thus formed itself being optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and alkyl radicals, themselves optionally substituted with one or more halogen atoms; and wherein 
 all of the above heterocycloalkyl and heteroaryl radicals are optionally substituted as indicated above, consist of from 4 to 10 ring members and contain from 1 to 3 heteroatoms chosen from O, S, N and NR10; and 
 R10 represents a hydrogen atom or an alkyl radical; 
 or an acid addition salt thereof. 
 
   
   
       2 ) The compound of formula (I) according to  claim 1 , wherein
 R represents a halogen atom;   or an acid addition salt thereof.   
   
   
       3 ) The compound of formula (I) according to  claim 1 , wherein
 R represents a hydrogen atom;   or an acid addition salt thereof.   
   
   
       4 ) The compound formula (I) according to  claim 1 , wherein:
 R1 and R6 are as defined in one of the alternatives i) to v);   NRaRb is such that either Ra and Rb, which may be identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms or a cycloalkyl radical, the alkyl and cycloalkyl radicals being optionally substituted with one or more halogen atoms, a hydroxyl radical or an NH 2 , NHalkyl or N(alkyl) 2  radical;   or Ra and Rb form, with the nitrogen atom to which they are attached, a cyclic amine that may optionally contain one or two other heteroatoms chosen from O, S, N or NR10, the cyclic amine thus formed itself being optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and alkyl radicals, themselves optionally substituted with one or more halogen atoms;   or an addition salt thereof.   
   
   
       5 ) The compound of formula (I) according to  claim 1 , wherein:
 R1 represents —X1-R7, wherein X1 represents —(CH 2 ) m — and R7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted;   and R6 represents a hydrogen atom or a hydroxyl, —(CH 2 ) m OH, —CO—NRaRb, —CH 2 —NRaRb, —CO 2 H, or —CO 2 alk radical;   and m, n and NRaRb are as defined in  claim 1 ;   or an acid addition salt thereof.   
   
   
       6 ) The compound of formula (I) according to  claim 1 , wherein:
 R1 represents —X2-R7, wherein X2 represents —O—, —O—(CH 2 ) m —, —CH(OH)—(CH 2 ) n —, —CO—, —CO—NRc-, —CO—NRc-O—, —CH(NRaRb)—, —C═NOH—, —C═N—NH 2 —, or —(CH 2 ) n1 —NRc-(CH 2 ) n2 —; and wherein R7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted;   R6 represents hydrogen;   and n, n1, n2, Rc and NRaRb are as defined in  claim 1 ;   or an acid addition salt thereof.   
   
   
       7 ) The compound of formula (I) according to  claim 1 , wherein either R1 represents —NRc-W, wherein W represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms which is linear or branched from 3 carbon atoms and optionally substituted with a radical chosen from —PO(OEt) 2 , —OH, —Oalk, —CF 3 , —CO—NR8R9 and SO 2 -alk, and R6 represents hydrogen, wherein when W represents a hydrogen atom, then z represents CO;
 or R1 represents —CH 2 —NRc-W, wherein W represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms which is linear or branched from 3 carbon atoms and optionally substituted with a radical chosen from —PO(OEt) 2 , —OH, —OEt, —CF 3 , —CO—N(alk) 2  and SO 2 -alk, and R6 represents hydrogen;   or R1 represents —CO—N(Rc)-OR′c and R6 represents hydrogen;   wherein Rc, R′c and NR8R9 are as defined in  claim 1 ,   or an addition salt thereof.   
   
   
       8 ) A compound of formula (I) according to  claim 1 , wherein:
 the ring (N) represents:   an azetidinyl or pyrrolidinyl ring substituted in the 3-position with R1 and R6, wherein R1 and R6 are as defined in  claim 1 ;   a piperidinyl or azepinyl ring substituted in the 3- or 4-position with R1 and R6, wherein R1 and R6 are as defined in  claim 1 ; or   a 8-azabicyclo(3,2,1)octan-3-yl, 6-azabicyclo[3.2.1]octan-3-yl or 3-azabicyclo[3.2.1]octan-8-yl ring;   or an acid addition salt thereof.   
   
   
       9 ) The compound of formula (I) according to  claim 1 , wherein the ring (N) represents a pyrrolidinyl ring substituted in the 3-position with R1 and R6 or the ring (N) represents a piperidinyl ring substituted in the 3- or 4-position with R1 and R6, wherein R1 and R6 are as defined in  claim 1 ;
 or an acid addition salt thereof.   
   
   
       10 ) The compound of formula (I) according to  claim 1 , wherein:
 the ring (N):   
     
       
         
         
             
             
         
       
     
     represents a pyrrolidinyl radical substituted in the 3-position with R1 and R6 or a piperidinyl ring substituted in the 3- or 4-position with R1 and R6,
 wherein R1 and R6 represent one of the following 5 alternatives i) to v): 
 i) R1 represents —X1-R7, wherein X1 represents —CH 2  and R7 represents a heterocycloalkyl, phenyl or heteroaryl ring, all optionally substituted; 
 and R6 represents a hydrogen atom or a the hydroxyl, —CH 2 OH, —CO—NRaRb or —CO 2 Et radical; 
 ii) R1 represents —X2-R7, wherein X2 represents: —O—, —CH(OH)—, —CH(OH)—CH 2 —, —CO—, —CH(NRaRb)—, —C═NOH—, —C═N—NH 2 —, or —(CH 2 ) n1 —NRc-(CH 2 ) n2 —; 
 and wherein R7 represents a heterocycloalkyl, phenyl or heteroaryl ring, all optionally substituted, 
 and R6 represents hydrogen; 
 iii) R1 represents —NRc-W, wherein W represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms which is linear or branched and optionally substituted with a radical chosen from —PO(OEt) 2 , —OH, —OEt, —CF 3 , —CO—NR8R9 and SO 2 -alk; 
 and R6 represents hydrogen; 
 wherein when W represents a hydrogen atom, then z represents CO; 
 iv) R1 represents —CH 2 —NRc-W, wherein W represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms which is linear or branched from 3 carbon atoms and optionally substituted with an SO 2 -alk radical; and R6 represents hydrogen; or 
 v) R1 represents —CO—N(Rc)-OR′c and R6 represents hydrogen; 
 n, n1 and n2, which may be identical or different, representing an integer from 0 to 2; 
 Rc and R′c, which may be identical or different, represent a hydrogen atom or an alkyl radical containing 1 or 2 carbon atoms; 
 NRaRb is such that either Ra and Rb, which may be identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms, optionally substituted with one or more halogen atoms, a hydroxyl radical or an NH 2 , NHalkyl or N(alkyl) 2  radical; 
 or Ra and Rb form, with the nitrogen atom to which they are attached, a morpholinyl or pyrrolidinyl radical optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and alkyl radicals, themselves optionally substituted with one or more halogen atoms; and wherein 
 all of the heterocycloalkyl, phenyl and heteroaryl radicals being optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms; the radicals hydroxyl, cyano or NR8R9; and the radicals alkyl, cycloalkyl, alkoxy, phenyl, heterocycloalkyl and heteroaryl, themselves optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and the radicals hydroxyl, alkoxy, CH 3 , —CH 2 OH, CN, CF 3 , OCF 3  or NRaRb; 
 R8 represents a hydrogen atom, a linear or branched alkyl radical containing at most 4 carbon atoms or a cycloalkyl radical containing from 3 to 6 ring members, alkyl and cycloalkyl themselves optionally substituted with one or more halogen atoms or a hydroxyl radical; 
 R9 represents a hydrogen atom or an alkyl radical optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms, and the radicals hydroxyl, alkoxy, NH 2 , NHalkyl, N(alkyl) 2 , phenyl, heterocycloalkyl and heteroaryl, themselves optionally substituted with one or more radicals chosen from halogen atoms and the radicals hydroxyl, OCH 3 , CH 3 , —CH 2 OH, CN, CF 3 , OCF 3 , NH 2 , NHalk and N(alk) 2 ; 
 or R8 and R9 form, with the nitrogen atom to which they are attached, a cyclic amine chosen from pyrrolyl, piperidyl, morpholinyl, pyrrolidinyl, azetidinyl and piperazinyl, optionally substituted with one or more alkyl radicals, themselves optionally substituted with one or more halogen atoms; 
 or an addition salt thereof. 
 
   
   
       11 ) The compound formula (I) according to  claim 1 , wherein:
 R2, R3 and R4, which may be identical or different, are such that one or R2, R3, and R4 represents a halogen atom or CF 3  and the other two, which may be identical or different, represent a hydrogen atom, a halogen atom or a methyl, methoxy, trifluoromethyl or trifluoromethoxy radical;   and R5 represents a hydrogen atom;   or an addition salt thereof.   
   
   
       12 ) The compound of formula (I) according to  claim 1 , wherein:
 R2, R3 and R4, which may be identical or different, are such that one of R2, R3, and R4 represents a fluorine atom and the other two, which may be identical or different, represent a hydrogen atom, a fluorine atom or a methyl radical; and   R5 represents a hydrogen atom;   or an acid addition salt thereof.   
   
   
       13 ) The compound of formula (I) according to  claim 1 , wherein
 Z represents SO 2 ;   or an acid addition salt thereof.   
   
   
       14 ) The compound of formula (I) according to  claim 1 , wherein
 Z represents CO;   or an acid addition salt thereof.   
   
   
       15 ) The compound of formula (I) according to  claim 1 , wherein:
 either R1 represents —X1-R7, wherein X1 represents —CH 2 —, and R6 represents a hydrogen atom or hydroxyl, CH 2 —OH, —CO—N(CH 3 ) 2 , —CO—NHCH 3 , —CO—NH—(CH 2 ) 2 —N(CH 3 ) 2  or —CO 2 Et radicals;   or R1 represents —X2-R7, wherein X2 represents —O—, —CHOH—, —CH(OH)—CH 2 —, —CO—, —CHNH 2 —, —NH—CH 2 —, —N(CH 3 )—CH 2 — or CH 2 —NH—CH 2 —, and R6 represents hydrogen;   R7 is chosen from pyrrolidinyl, piperidinyl, piperazinyl, pyrimidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuran, phenyl, pyridyl, thienyl, thiazolyl, dithiazolyl, pyrazolyl, pyrazinyl, furyl, imidazolyl, pyrrolyl, oxazolyl, isoxazolyl, benzodihydrofuranyl, benzoxodiazolyl, benzothiodiazolyl, benzothienyl, quinolyl, and isoquinolyl radicals;   all the radicals represented by R7 are optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and the radicals hydroxyl, methyl, methoxy, hydroxymethyl, alkoxymethyl, cyano, NH 2 , NHalk, N(alk) 2 , —CH 2 —NH 2 , —CH 2 —NHalk, —CH 2 —N(alk) 2 , phenyl, morpholinyl and CH2-morpholinyl, themselves optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and the radicals hydroxyl, CH 3 , OCH 3 , —CH 2 OH, CN, CF 3 , OCF 3 , NH 2 , NHalk and N(alk) 2 ;   or an acid addition salt thereof.   
   
   
       16 ) The compound of formula (I) according to  claim 1 , selected from the group consisting of:
 {4-[4-(4-fluorophenylamino)pyrimidin-2-ylamino]phenyl}-[4-(methyloxazol-2-ylmethylamino)piperidin-1-yl]methanone;   {4-[4-(4-fluorophenylamino)pyrimidin-2-ylamino]phenyl}-[3-(methyl-1H-pyrrole-2-ylmethylamino)piperidin-1-yl]methanone;   1-{4-[4-(4-fluorophenylamino)pyrimidin-2-ylamino]-benzoyl}-3-pyridin-3-ylmethylpiperidine-3-carboxylic acid methylamide;   N-4-(4-fluoro-3-methylphenyl)-N-2-(4-{3-[(2-methanesulphonylethylamino)methyl]pyrrolidine-1-sulphonyl}-phenyl)pyrimidine-2,4-diamine;   N-4-(4-fluoro-3-methylphenyl)-N-2-[4-(3-{[(1-methyl-1H-pyrrol-2-ylmethyl)amino]methyl}pyrrolidine-1-sulphonyl)phenyl]pyrimidine-2,4-diamine;   4-pyrrolidin-1-ylmethyl-1-{4-[4-(4-fluoro-3-methylphenylamino)pyrimidin-2-ylamino]benzenesulphonyl}-piperidin-4-ol;   {4-[4-(4-fluoro-3-methylphenylamino)pyrimidin-2-ylamino]phenyl}-[4-(methylpyridin-2-ylmethylamino)piperidin-1-yl]methanone;   {4-[4-(4-fluoro-3-methylphenylamino)pyrimidin-2-ylamino]phenyl}-[4-(methylpyridin-4-ylmethylamino)piperidin-1-yl]methanone;   {4-[(1,5-dimethyl-1H-pyrazol-4-ylmethyl)methylamino]piperidin-1-yl}-{4-[4-(4-fluoro-3-methylphenylamino)pyrimidin-2-ylamino]phenyl}methanone;   {4-[(2-aminopyridin-3-ylmethyl)methylamino]piperidin-1-yl}-{4-[4-(4-fluoro-3-methylphenylamino)pyrimidin-2-ylamino]phenyl}methanone;   4-{[(1-{4-[4-(4-fluoro-3-methylphenylamino)pyrimidin-2-ylamino]benzoyl}piperidin-4-yl)methylamino]methyl}-1,5-dimethyl-1H-pyrrole-2-carbonitrile;   {4-[(2,4-dimethylthiazol-5-ylmethyl)methylamino]piperidin-1-yl}-{4-[4-(4-fluoro-3-methylphenylamino)pyrimidin-2-ylamino]phenyl}methanone; and   (1-{[4-({4-[(4-fluorophenyl)amino]pyrimidin-2-yl}amino)phenyl]sulphonyl}piperidin-4-yl)(pyridin-3-yl)-methanamine;   or an addition salt thereof.   
   
   
       17 ) A process for preparing a compound of formula (Ia): 
     
       
         
         
             
             
         
       
       wherein R is as defined in  claim 1  for the compounds of formula (I) and R 1 ′, R 2 ′, R 3 ′, R 4 ′, R 5 ′ and R 6 ′ are as defined in  claim 1  for R2, R3, R4, R5, and R6 respectively, in which the possible reactive functions are optionally protected, 
       said process comprising: 
       reacting a compound of formula (II): 
     
     
       
         
         
             
             
         
       
       wherein R and R 5 ′ are as defined above, 
       with a compound of formula (III): 
     
     
       
         
         
             
             
         
       
       wherein R2′, R3′ and R4′ are as defined above, 
       so as to obtain a product of formula (IV): 
     
     
       
         
         
             
             
         
       
       wherein R, R 2 ′, R 3 ′, R 4 ′ and R 5 ′ are as defined above; 
       reacting the compound of formula (IV) with the aniline of formula (V): 
     
     
       
         
         
             
             
         
       
       so as to obtain a product of formula (VI): 
     
     
       
         
         
             
             
         
       
       wherein R, R 2 ′, R 3 ′, R 4 ′ and R 5 ′ are as defined above; 
       reacting the compound of formula (VI) with chlorosulphonic acid SO 2 (OH)Cl so as to obtain the corresponding product of formula (VII): 
     
     
       
         
         
             
             
         
       
       wherein R, R 2 ′, R 3 ′, R 4 ′ and R 5 ′ are as defined above; and 
       reacting the compound of formula (VII) with an amine of formula (VIII): 
     
     
       
         
         
             
             
         
       
       wherein R 1 ′ and R 6 ′ are as defined above, 
       so as to obtain a product of formula (Ia); and 
       optionally subjecting the compound of formula (Ia) to one or more of the following conversion reactions in any order:
 a) a reaction of oxidation of an alkylthio group to the corresponding sulphoxide or sulphone group, 
 b) a reaction of conversion of an alkoxy function to a hydroxyl function, or else of a hydroxyl function to an alkoxy function, 
 c) a reaction of oxidation of an alcohol function to an aldehyde or ketone function, 
 d) a reaction of removal of the protective groups that may be borne by the protected reactive functions, 
 e) a salification reaction with an inorganic or organic acid so as to obtain the corresponding salt, and 
 f) a reaction to resolve the racemic forms into resolved products. 
 
     
   
   
       18 ) A process for preparing a compound of formula (Ib): 
     
       
         
         
             
             
         
       
       wherein R is as defined in  claim 1  for the compound of formula (I), and R 1 ′, R 2 ′, R 3 ′, R 4 ′, R 5 ′ and R 6 ′ are as defined in  claim 1  for R2, R3, R4, R5, and R6 respectively, in which the possible reactive functions are optionally protected, 
       reacting a compound of formula (II): 
     
     
       
         
         
             
             
         
       
       wherein R and R 5 ′ are as defined above, 
       with a compound of formula (III): 
     
     
       
         
         
             
             
         
       
       wherein R, R 2 ′, R 3 ′, and R 4 ′ are as defined above, 
       so as to obtain a product of formula (IV): 
     
     
       
         
         
             
             
         
       
       wherein R, R 2 ′, R 3 ′, R 4 ′ and R 5 ′ are as defined above; 
       reacting the compound formula (IV) with 4-aminobenzoic acid methyl ester so as to obtain the product of formula (IX): 
     
     
       
         
         
             
             
         
       
       in which R, R 2 ′, R 3 ′, R 4 ′ and R 5 ′ are as defined above; and 
       saponifying the compound formula (IX) to its corresponding acid of formula (X): 
     
     
       
         
         
             
             
         
       
       wherein R, R 2 ′, R 3 ′, R 4 ′ and R 5 ′ are as defined above; 
       reacting the compound of formula (X) with an amine of formula (VIII) as defined above: 
       so as to obtain a product of formula (Ib): 
     
     
       
         
         
             
             
         
       
       in which R, R 1 ′, R 2 ′, R 3 ′, R 4 ′, R 5 ′, and R 6 ′ are as defined above; and 
       optionally subjecting the compound of formula (Ib) to one or more of the following conversion reactions in any order:
 a) a reaction of oxidation of an alkylthio group to the corresponding sulphoxide or sulphone group, 
 b) a reaction of conversion of an alkoxy function to a hydroxyl function, or else of a hydroxyl function to an alkoxy function, 
 c) a reaction of oxidation of an alcohol function to an aldehyde or ketone function, 
 d) a reaction of removal of the protective groups that may be borne by the protected reactive functions, 
 e) a salification reaction with an inorganic or organic acid so as to obtain the corresponding salt, and 
 f) a reaction to resolve the racemic forms into resolved products. 
 
     
   
   
       19 ) A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
   
   
       20 ) A pharmaceutical composition comprising a compound according to  claim 16  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
   
   
       21 ) A method of inhibiting the activity of the protein kinase IKK comprising contacting said protein kinase with a compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       22 ) The method according to  claim 21 , wherein the protein kinase is in a mammal. 
   
   
       23 ) A method of treating or preventing a disease selected from inflammatory diseases, diabetes and cancer, comprising administering to a patient in need of said treatment or prevention a therapeutically effective amount of compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       24 ) The method according to  claim 23  wherein the disease is cancer. 
   
   
       25 ) The method according to  claim 24  wherein the cancer is resistant to cytotoxic agents.